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Unlike antigen introduced systemically, the development of immune responses against antigen at barrier surfaces is relatively poorly studied. It is clear, however, that tissue resident dendritic cells (DC) play a central role. They are capable of acquiring antigen and migrating to regional lymph node (LN) where they activate T cells and thereby initiate adaptive immune responses. Commensal organisms at barrier sites, however, are tolerated by the immune system. Since antigens from these organisms are not present in the thymus where central tolerance is established, responses against commensal organisms are limited through the development of peripheral tolerance. This process is incompletely understood, but appears to rely on specialized DC sub-populations that actively inhibit antigen-specific T cell responses in the regional LN.The lab’s focus is the early events after antigen exposure in the skin that allows for the development of appropriate immune responses to pathogens while limiting responses directed against commensal organisms. We are concentrating on two opposing dendritic cell (DC) subsets in the skin. We have previously shown that DC in the epidermis (the outermost layer of skin), termed Langerhans cells (LC) suppress the development of skin immune responses while DC that reside deeper in the skin, dermal DC, are required for the development of skin immune responses. This is consistent with a model in which LC specialize in limiting effector responses against commensal organisms. According to this model, antigen found exclusively in the epidermis is presented by LC leading to no response or tolerance and thereby prevents deleterious immune responses against commensal organisms. For invasive pathogens which penetrates through the epidermis, antigen is present in both the epidermis and dermis. In this situation antigen is acquired by both dermal DC which are responsible for the generation of effector responses, and by epidermal LC which inhibit that response.We have engineered mice that have either constitutive or inducible depletion of LC. We have also employed Cre-lox systems to constitutively or inducibly ablate genes of interest selectively in LC. By combining these unique strains of mice with models of skin inflammation such as allergic contact dermatitis and infection, we are able to examine the function of Langerhans cells and the molecular mechanisms underlying these functions.